Neutrophil CEACAMs and the inflammatory response to Neisseria gonorrhoeae

Background: Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are proteins that mediate intercellular adhesion, intracellular signaling, and microbial recognition. Of the CEACAMs made by human neutrophils, CEACAMs 1, 3, and 6 are receptors for opacity-associated (Opa) outer membrane proteins of the bacterial pathogen Neisseria gonorrhoeae, which drive their non-opsonic phagocytosis. Summary: This Review describes what is currently known about CEACAM subcellular localization, bacterial recognition, and downstream signaling events in human neutrophils in response to N. gonorrhoeae, and the experimental systems used to elucidate them. It highlights the consequences of these activities on neutrophil activation and killing of N. gonorrhoeae, particularly those downstream of CEACAM3. The potential cross-talk between CEACAMs and with other neutrophil receptors, and how these signals may impact responses to N. gonorrhoeae, are also covered. Key Messages: Most Opa proteins of N. gonorrhoeae bind CEACAM1, with a subset also binding CEACAM3. Neutrophil CEACAM binding stimulates signaling events that drive phagocytosis of Opa-expressing N. gonorrhoeae, accompanied by degranulation, oxidant production, and proinflammatory signaling and transcriptional responses. In particular, CEACAM3 ligation leads to rapid phagocytic killing of N. gonorrhoeae. N. gonorrhoeae can avoid CEACAM3-mediated clearance by phase variation to turn off Opa protein expression or producing non-CEACAM3-binding Opa proteins. It can also bind host-derived complement C4b-binding protein (C4BP) and sialic acid, to impede CEACAM3-Opa interaction and engage sialic acid-binding immunoglobulin-like lectins (Siglecs) that transduce inhibitory signals to dampen CEACAM3 signaling, respectively.